No cross-tolerance between S-nitrosocaptopril and nitroglycerin in dog coronary arteries in vivo.
S-Nitrosocaptopril (S-NO-Cap), a nitrate and an angiotensin-converting enzyme (ACE) inhibitor, may be produced after coadministration of nitroglycerin (NTG) and captopril (CAP). We synthesized S-NO-Cap and investigated its in vivo tolerance. In open-chest dogs, S-NO-Cap [300 microg; intracoronary (i.c.)] and NTG (50 microg, i.c.) increased coronary blood flow (CBF) similarly (8.0 vs. 9.0 ml/min; p = NS; n = 5). After a 2-h i.c. NTG infusion at high dose (1.32 micromol/min), NTG (50 microg, i.c.) had no significant effect on CBF, whereas S-NO-Cap (300 microg, i.c.) still produced an attenuated increase in CBF (4.9 ml/min; p < 0.05 vs. control). On the other hand, after a 2-h i.c. infusion of S-NO-Cap (1.32 micromol/min), the CBF response to S-NO-Cap (300 microg) showed no attenuation, whereas that to NTG (50 microg) was potentiated (8.8 vs. 12.6 ml/min; p < 0.05; n = 6). Under basal conditions, S-NO-Cap (30-300 microg, i.c.) increased CBF dose dependently, whereas CAP (30-300 microg, i.c.) had no effect on CBF, suggesting that S-NO-Cap dilates coronary vessels by a nitrate action but not by an ACE-inhibitory action. In nonsurgical dogs, 2-h intravenous (i.v.) infusion of S-NO-Cap (1.32 micromol/min) had a stable hypotensive effect, whereas that of NTG (1.32 micromol/min) gradually attenuated the effect. Plasma NO3-, an oxidative product of nitric oxide (NO), increased after both infusions, suggesting that S-NO-Cap may act partially as an NO donor, similarly to NTG. Plasma ACE activity was reduced after an S-NO-Cap infusion (5.84 vs. 4.10 IU/L; p < 0.01; n = 5), and plasma aldosterone was markedly increased after NTG infusion relative to that after S-NO-Cap infusion (243.0 vs. 38.6 pg/ml; p < 0.05). Plasma norepinephrine increased after both infusions (393.6 vs. 289.0 pg/ml; p = NS). As judged by the increase in CBF, whereas S-NO-Cap showed partial tolerance with NTG, no tolerance was found with S-NO-Cap itself. The in vivo coronary vascular response to S-NO-Cap may, therefore, be partially reduced by activation of the adrenergic or renin-angiotensin-aldosterone systems or both induced by NTG, because S-NO-Cap showed no cross-tolerance with NTG in our earlier in vitro study.
Takaoka
A
A
First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Japan.
Nakae
I
I
Takahashi
M
M
Matsumoto
T
T
Liu
Q
Q
Mitsunami
K
K
Kinoshita
M
M
D000450:Aldosterone / Q000097:blood; D000818:Animals; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D006152:Cyclic GMP / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D009638:Norepinephrine / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D012083:Renin / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology*
D009566:Nitrates; D014665:Vasodilator Agents; C060039:S-nitrosocaptopril; D009569:Nitric Oxide; D000450:Aldosterone; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D005996:Nitroglycerin; D006152:Cyclic GMP; D009638:Norepinephrine